While there is considerable information about conventional T cells in hepatitis C virus (HCV) infection, less is known about other cell types present within the liver, which contains large numbers of less conventional cells, including natural killer T (NK T) cells. There is mounting evidence that failure of the immune response early in HCV infection is associated with persistent infection, yet little attention has been paid to innate immunity, which is presumably critical to the outcome of infection. An NKT cell subset, CDld-reactive T cells, and the ligand CDld have been highly conserved across mammalian evolution. These cells have an important regulatory role in initiation and control of both protective and pathologic immune responses. The functional activities of CDld-reactive NKT cells, from various sites, are dramatically different, presumably reflective of distinct physiological roles. While bone marrow derived CDld-reactive NK T cells produce large amounts of anti-inflammatory cytokines, the corresponding liver population in patients with chronic HCV has the opposite pro-inflammatory polarity. Remarkably, a substantial fraction of human intrahepatic lymphocytes (IHL) is CDld-reactive NKT cells. We hypothesize that failure of NKT to produce adequate IFN-gamma during acute infection facilitates the persistence of HCV. Since the ability to examine both peripheral and liver compartments during acute infection is limited in patients with HCV, we propose to examine CDld-reactive NKT cells in the only animal model of HCV, the chimpanzee, before, during, and after infection. To accomplish this we will utilize samples obtained from chimpanzees already under study in AI048231 to: 1) determine the frequency and effector function of CD1d reactive NK T cells before, during and after acute infection to determine whether there is functional impairment of these cells; 2) determine whether NKT cells serve as pro-inflammatory cells in the chronic phase of HCV hepatitis and contribute to liver injury; and 3) determine whether there is compartmentalization of CDld reactive NK T cells and the kinetics of this compartmentalization. Results of these studies, in synergy with the characterization of the conventional immune response by our collaborators on AI048231, will help us understand why HCV is persistent in the majority of infected patients and might suggest new therapeutic targets.